Topical application of ivermectin for the treatment of dermatological conditions/afflictions

ABSTRACT

Dermatological conditions/afflictions such as rosacea, common acne, seborrheic dermatitis, perioral dermatitis, acneform rashes, transient acantholytic dermatosis, and acne necrotica miliaris, most notably rosacea, are treated by topically applying onto the affected skin area of an individual in need of such treatment, a topical pharmaceutical composition which comprises a thus effective amount of ivermectin.

CROSS-REFERENCE TO EARLIER APPLICATIONS

This application is a continuation of earlier U.S. patent applicationSer. No. 12/483,604, filed Jun. 12, 2009, now U.S. Pat. No. 8,093,219,which is a continuation of U.S. patent application Ser. No. 11/255,910,filed Oct. 24, 2005, now U.S. Pat. No. 7,550,440, which is acontinuation of International Application No. PCT/EP2004/004950, filedApr. 22, 2004 and designating the United States (published in theEnglish language on Nov. 4, 2004 as WO 2004/093886 A1), which claimsbenefit of U.S. Provisional Application No. 60/468,994, filed May 9,2003, and also claims priority under 35 U.S.C. §119 of application Ser.No. 03/05048, filed in France on Apr. 24, 2003, each earlier applicationhereby expressly incorporated by reference herein and each assigned tothe assignee hereof.

CROSS-REFERENCE TO RELATED APPLICATION

Application Ser. No. 12/468,287, filed May 19, 2009, now allowed, isalso a continuation of earlier U.S. patent application Ser. No.11/255,910, filed Oct. 24, 2005, now U.S. Pat. No. 7,550,440, based onthe same earlier domestic and foreign applications as identified above,said application Ser. No. 12/468,287 also hereby expressly incorporatedby reference herein and assigned to the assignee hereof.

BACKGROUND OF THE INVENTION

1. Technical Field of the Invention

The present invention relates to the formulation of ivermectin intotopical pharmaceutical compositions useful for the treatment of rosacea.This invention also relates to topical pharmaceutical compositionssuited for administration to humans, comprising ivermectin.

2. Description of Background and/or Related and/or Prior Art

Ivermectin is a mixture of two compounds belonging to the avermectinclass, 5-O-demethyl-22,23-dihydroavermectin A_(1a) and5-O-demethyl-22,23-dihydroavermectin A_(1b). They are also known as22,23-dihydroavermectin B_(1a) and 22-23-dihydroavermectin B_(1b).Ivermectin contains at least 80% of 22,23-dihydroavermectin B_(1a) andless than 20% of 22,23-dihydroavermectin B_(1b). This active agent ispart of the avermectin class, a group of macrocyclic lactones producedby the bacterium Streptomyces avermitilis (Reynolds JEF (Ed) (1993)Martindale). The extra pharmacopoeia, 29^(th) Edition, PharmaceuticalPress, London).

In the middle of the 1980s, ivermectin was presented as a broad-spectrumanti-parasitic medicinal product for veterinary use (W. C. CAMPBELL, etal., (1983). Ivermectin: a potent new anti-parasitic agent, Science,221, 823-828). It is effective against most common intestinal worms(except tapeworms), most acarids and some lice. It in particularexhibits considerable affinity for the glutamate-dependent chloridechannels present in invertebrate nerve cells and muscle cells. Itsbinding to these channels promotes an increase in membrane permeabilityto chloride ions, resulting in hyperpolarization of the nerve or musclecell. Neuromuscular paralysis which can lead to the death of certainparasites results therefrom. Ivermectin also interacts with otherligand-dependent chloride channels, such as those involving theneuromediator GABA (gamma-aminobutyric acid).

Ivermectin is more particularly an anthelmintic. It has already beendescribed in humans in the treatment of river blindness caused byOnchocerca volvulus, of gastrointestinal strongyloidiasis(anguillulosis) (product Stromectol®), and of human scabies (Meinking TL et al., N. Engl. J. Med. , 1995 Jul. 6; 333(1):26-30, “The treatmentof scabies with ivermectin”) and also in the treatment ofmicrofilaraemia diagnoses or suspected in individuals suffering fromlymphatic filariasis due to Wuchereria bancrofti.

U.S. Pat. No. 6,133,310 discloses the use of ivermectin topically in theform of a prototype of a lotion consisting of a mixture of ivermectinand water, and also mentions the possibility of a prototype of a creamconsisting, for its part, of a mixture of ivermectin and an excipientsuch as propylene glycol or sodium lauryl sulfate, but describes nopharmaceutical composition as such. These mixtures are similar toexperimental preparations used in the context of initial results ofproof of concept. In fact, the elements disclosed in that patent provideno teaching to those skilled in the art regarding the feasibility ofindustrially acceptable pharmaceutical compositions containingivermectin, in particular having good cosmetic properties and ashelf-life which is sufficiently long for an industrial pharmaceuticalproduct (minimum of 2 years).

SUMMARY OF THE INVENTION

Despite the fact that all these uses in humans are limited to oraladministration or to the use of experimental preparations, topicalpharmaceutical compositions have now been developed suited for thetreatment of humans, containing ivermectin. In addition, it has now beenfound that the compositions according to the invention exhibit very goodstability, in particular at different pHs, and good tolerance on theskin. In fact, it has now been found that same are particularly suitablefor the treatment of dermatological conditions, and more particularlywell suited for the treatment of rosacea.

The present invention also features the formulation of ivermectin intotopical pharmaceutical compositions useful for the treatment of rosacea,topical pharmaceutical compositions suited for human administration,comprising ivermectin, and the use of these topical pharmaceuticalcompositions for the treatment of rosacea (whether regime or regimen).

DETAILED DESCRIPTION OF BEST MODE AND SPECIFIC/PREFERRED EMBODIMENTS OFTHE INVENTION

The ivermectin according to the invention contains at least 80% of22,23-dihydroavermectin B_(1a) and less than 20% of22,23-dihydroavermectin B_(1b).

The pharmaceutical compositions according to the invention are suitedfor treating the skin and may be in liquid, pasty or solid form, andmore particularly in the form of ointments, creams, milks, pomades,powders, impregnated pads, syndets, towelettes, solutions, gels, sprays,foams, suspensions, lotions, sticks, shampoos or washing bases. They mayalso be in the form of suspensions of microspheres or nanospheres or oflipid or polymeric vesicles or of polymeric patches and of hydrogels forcontrolled release. These compositions for topical application may be inanhydrous form, in aqueous form of in the form of an emulsion.

In a preferred embodiment of the invention, the pharmaceuticalcompositions according to the invention are in the form of an emulsionof the cream or lotion type, of a gel, or of a solution.

More preferably, the compositions according to the invention are in theform of an emulsion.

Conventional emulsions as described in the prior art are unstablevirtually homogeneous systems of two immiscible liquids, one of which isdispersed in the other in the form of fine droplets (micelles). Thisdispersion is stabilized by virtue of the action ofsurfactant-emulsifiers which modify the structure and the ratio of theforces at the interface, and therefore increase the stability of thedispersion by decreasing the interface tension energy.

Surfactant-emulsifiers are amphiphilic compounds which possess ahydrophobic component having affinity for oil and a hydrophiliccomponent having affinity for water, thus creating a link between thetwo phases. Ionic or nonionic emulsifiers therefore stabilize oil/wateremulsions by adsorbing to the interface and forming lamellar layers ofliquid crystals.

The emulsifier power of nonionic surfactants is closely linked to thepolarity of the molecule. This polarity is defined by the HLB(hydrophilic/lipophilic balance). Conventional emulsions are generallystabilized by a mixture of surfactants, the HLBs of which can be quitedifferent but the proportion of which in the mixture corresponds to therequired HLB of the fatty phase to be emulsified.

The compositions according to the invention will contain this type ofingredient.

The compositions according to the invention are described as stableemulsions in that they exhibit good physical and chemical stability overtime, even at a temperature above ambient temperature (for example45-55° C.), as shown in the examples described hereinafter.

The ivermectin in the compositions according to the invention also,surprisingly, exhibits good chemical stability in the case of pHvariation.

The compositions according to the invention are advantageously emulsionswhich comprise:

a) an oily phase comprising fatty substances;

b) at least one surfactant-emulsifier;

c) ivermectin;

d) one or more solvent(s) and/or propenetrating agent(s) for the activeagent;

e) and water.

More particularly, the compositions according to the invention areemulsions which comprise:

a) an oily phase comprising fatty substances;

b) at least one surfactant-emulsifier;

c) ivermectin;

d) one or more solvent(s) and/or propenetrating agent(s) for the activeagent;

e) one or more gelling agent(s);

f) and water.

The oily phase of the composition according to the invention maycomprise, for example, vegetable, mineral, animal or synthetic oils,silicone oils, Guerbet alcohols or other substances, and mixturesthereof.

As an example of a mineral oil, mention may be made, for example, ofparaffin oils of various viscosities, such as Primol 352, Marcol 82 orMarcol 152 marketed by Esso.

As a vegetable oil, mention may be made of sweet almond oil, palm oil,soybean oil, sesame oil and sunflower oil.

As an animal oil, mention may be made of lanolin, squalene, fish oil andmink oil.

As a synthetic oil, mention may be made of esters, such as cetearylisononanoate marketed in particular under the name Cetiol SN by CognisFrance, diisopropyl adipate, for instance the product marketed under thename Ceraphyl 230 by ISF, isopropyl palmitate, for instance the productmarketed under the name Crodamol IPP by Croda, or caprylic caprictriglyceride such as Miglyol 812 marketed by Huls/Lambert Rivière.

As a silicone oil, mention may be made of a dimethicone, such as theproduct marketed under the name Dow Corning 200 fluid, or acyclomethicone, such as the product marketed under the name Dow Corning244 fluid by Dow Corning, or the product marketed under the name MirasilCM5 by SACI-CFPA.

As other fatty substances, mention may be made of fatty acids such asstearic acid, fatty alcohols such as stearyl alcohol, cetostearylalcohol and cetyl alcohol, or derivatives thereof, waxes such asbeeswax, carnauba wax or candelilla wax, and also gums, in particularsilicone gums.

The ingredients of the oily phase may be selected in a varied manner bythose skilled in the art in order to prepare a composition having thedesired properties, for example of consistency or of texture.

The oily phase of the composition according to the invention preferablycomprises a synthetic oil and/or a silicone oil; as synthetic oil,isopropyl palmitate such as the product marketed under the name CrodamolIPP by Croda or isopropyl myristate such as the product marketed underthe name Crodamol IPM by Croda is preferred; as silicone oil, adimethicone is preferred.

The oily phase of the emulsion according to the invention may be presentat a content of from 3 to 50% by weight relative to the total weight ofthe composition, and preferably from 6 to 20% by weight.

The compositions according to the invention containsurfactant-emulsifiers. Among these compounds, mention may be made, byway of examples, of the glyceryl/PEG 100 stearate marketed under thename Arlacel 165FL by UNIQEMA or under the name Simulsol 165 by SEPPIC;polyoxyethylenated fatty acid esters such as Arlatone 983 from thecompany UNIQEMA or the polyoxyethylenated (2) stearyl alcohol marketedunder the name Brij72 combined with the polyethylenated (21) stearylalcohol marketed under the name Brij721 by UNIQEMA; sorbitan esters suchas the sorbitan oleate marketed under the name Arlacel 80 by ICI ormarketed under the name Crill 4 by Croda, the sorbitan sesquioleatemarketed under the name Arlacel 83 by ICI or marketed under the nameMontane 83 by SEPPIC, or else sorbitan isostearate; fatty alcoholethers.

The compositions according to the invention advantageously comprise upto 15% by weight of suitable surfactant-emulsifier, preferably from 2 to12% by weight, and more particularly from 2 to 6% by weight, relative tothe total weight of the composition.

The compositions according to the invention comprise from 0.001 to 10%of ivermectin by weight relative to the total weight of the composition.Preferably, the compositions according to the invention contain from 0.1to 5% of ivermectin by weight relative to the total weight of thecomposition.

By way of example of a solvent and/or propenetrating agent for theivermectin active agent, mention will preferably be made of propyleneglycol, alcohols such as ethanol, isopropanol, butanol,N-methyl-2-pyrrolidone or DMSO, polysorbate 80, phenoxyethanol, andmixtures thereof.

The table below illustrates the solubility of ivermectin in varioussolvents:

Maximum % solubility of ivermectin in the solvent Solvents concerned(weight/weight) Triacetin 7.22 Propylene glycol 21.83N-methyl-2-pyrrolidone 58.13 Propylene glycol/oleyl alcohol (4 27.31parts/2 parts)

The compositions of the invention contain from 0.1 to 20%, andpreferably from 1 to 10%, of a solvent and/or propenetrating agent forthe ivermectin active agent.

The compositions according to the invention may also comprise aqueousphase gelling compounds ranging from 0.01 to 5% by weight relative tothe total weight of the composition. Among the gelling agents which canbe used in the composition according to the invention, mention may bemade of carboxyvinyl polymers (carbomers) and, by way of non-limitingexamples, of carbomer, Carbopol 981, Carbopol ETD 2020, Carbopol 980,Carbopol Ultrez 10 NF and Pemulen TR1, marketed by NOVEON.

As aqueous phase gelling agents, mention may also be made of cellulosederivatives such as, for example, hydroxypropylmethylcellulose orhydroxyethylcellulose; xanthan gums, aluminum/magnesium silicates suchas Veegum K or Veegum Ultra remarketed by Vanderbilt, guar gums and thelike, polyacrylamides such as the mixture polyacrylamide/C13-14isoparaffin/laureth-7, for instance that marketed, for example, bySEPPIC under the name Sepigel 305, or the mixture acrylamide, AMPScopolymer dispersion 40%/isohexadecane under the name Simulgel 600PHA,or the family of modified starches such as Structure Solanace remarketedby National Starch, or mixtures thereof.

The compositions of the invention preferentially contain from 0.01 to5%, and preferably from 0.1 to 3%, of gelling agent.

As gelling agent according to the invention, use will preferably be madeof carbomers, and preferably Pemulen TR1 or aluminum/magnesium silicassuch as Veegum K.

The compositions of the invention also contain water ranging from 30 to95%, and preferably from 60 to 80%, by weight relative to the totalweight of the composition. The water used in the composition accordingto the invention will preferably be purified water.

The pharmaceutical compositions according to the invention may alsocontain inert additives or combinations of these additives, such as

-   -   flavor enhancers;    -   preservatives;    -   stabilizers;    -   humidity regulators;    -   pH regulators;    -   osmotic pressure modifiers;    -   UV-A and UV-B screening agents;    -   and antioxidants.

Of course, one skilled in this art will take care to choose the optionalcompound(s) to be added to these compositions in such a way that theadvantageous properties intrinsically associated with the presentinvention are not, or are not substantially, altered by the envisagedaddition.

These additives may be present in the composition at from 0.001 to 20%by weight relative to the total weight of the composition.

The compositions according to the invention are advantageously emulsionswhich comprise:

a) 6 to 20% of an oily phase;

b) 2 to 12% of a surfactant-emulsifier;

c) 0.1 to 5% of ivermectin;

d) 0.1 to 20% of solvent;

e) 0.01 to 5% of gelling agents;

f) and water.

The pH will preferably range from 6.0 and 6.5. Verification of thenatural pH of the mixture and possible correction with a solution of aneutralizing agent, and also the incorporation of the optionaladditives, may be carried out, according to their chemical nature,during one of the steps of the method of preparation, described above.

Examples of compositions according to the present invention areillustrated in Examples 1 to 6 to follow.

The present invention also features topical compositions suited forhuman use, characterized in that they are emulsions comprising:

a) an oily phase comprising fatty substances;

b) at least one surfactant-emulsifier;

c) ivermectin;

d) one or more solvent(s) and/or propenetrating agent(s) for the activeagent;

e) and water.

More particularly, this composition may comprise:

a) an oily phase comprising fatty substances;

b) at least one surfactant-emulsifier;

c) ivermectin;

d) one or more solvent(s) and/or propenetrating agent(s) for the activeagent;

e) one or more gelling agent(s);

f) and water.

Preferably, the composition comprises:

a) 6 to 20% of an oily phase;

b) 2 to 12% of a surfactant-emulsifier;

c) 0.1 to 5% of ivermectin;

d) 0.1 to 20% of solvent;

e) 0.01 to 5% of gelling agents;

f) and water.

The ingredients being as defined above.

This invention also features formulation of the compositions accordingto the invention into pharmaceutical preparations useful to treatdermatological conditions/afflictions.

The formulation of ivermectin into topical pharmaceutical compositionsfor human use according to the invention is particularly useful for thetreatment of rosacea, of common acne, of seborrhoeic dermatitis, ofperioral dermatitis, of acneform rashes, of transient acantholyticdermatosis, and of acne necrotica miliaris.

The formulation of ivermectin into topical pharmaceutical compositionsfor human use according to the invention is more particularly useful ina regime or regimen for the treatment of rosacea.

In order to further illustrate the present invention and the advantagesthereof, the following specific examples of compositions comprisingivermectin and the stability and tolerance thereof are given, it beingunderstood that same are intended only as illustrative and in nowiselimitative. In said examples to follow, all parts and percentages aregiven by weight, unless otherwise indicated.

EXAMPLE 1 Composition 1

The Compositions of Examples 1 to 4 are Formulated According to theFollowing Procedure

In a first suitable container, weigh the aqueous phase, mix at 700 rpmand heat to 65°-70° C.

In a second suitable container, weigh the oily phase, mix at 425-475 rpmand heat to 70°-75° C.

In a third suitable container, weigh the active phase and heat to 60-65°C.

Where the oily and aqueous phases are at 70° C., mix the two phases withRayneri stirring at 900 rpm until complete homogeneity, and then cool.

Allow the emulsion to cool to 55-60° C., add the active phase withstirring at 600 rpm. Decrease, at 600 rpm, to 30° C.

Adjust the pH to 6.0.

% by weight relative to the total weight of the Ingredients compositionIvermectin 1.00 Glycerol 4.0 Aluminum magnesium silicate 1.0 Methylpara-hydroxybenzoate 0.2 Disodium EDTA 0.05 Citric acid monohydrate 0.05Isopropyl palmitate 4.0 Glyceryl/PEG 100 stearate 3.0 Self-emulsifiablewax 2.0 Palmitostearic acid 2.5 Steareth-20 3.0 Sorbitan stearate 2.0Dimethicone 20 0.5 Propyl para-hydroxybenzoate 0.1 Propylene glycol 4.0Glyceryl triacetate 1.0 Phenoxyethanol 0.5 10% sodium hydroxide qs pHWater qs 100

EXAMPLE 2 Composition 2

% by weight relative to the total weight of the Ingredients compositionIvermectin 1.00 Glycerol 4.0 Steareth-2 1.0 Steareth-21 2.0 Aluminummagnesium silicate/titanium 1.0 dioxide/silica Methylpara-hydroxybenzoate 0.2 Propyl para-hydroxybenzoate 0.1 Disodium EDTA0.05 Citric acid monohydrate 0.05 Isopropyl palmitate 4.0 Glyceryl/PEG100 stearate 2.0 Self-emulsifiable wax 1.0 Palmitostearic acid 2.00Dimethicone 200-350 cS 0.5 Propylene glycol 4.0 Glyceryl triacetate 1.00Phenoxyethanol 0.5 10% sodium hydroxide qs pH Water qs 100

EXAMPLE 3 Composition 3

% by weight relative to the total weight of the Ingredients compositionIvermectin 1.00 Glycerol 4.0 Acrylate C10-30 alkyl acrylate 0.15crosspolymer Methyl para-hydroxybenzoate 0.2 Disodium EDTA 0.05 Citricacid monohydrate 0.05 Isopropyl myristate 4.0 Cetyl alcohol 3.0 Stearylalcohol 2.0 Self-emulsifiable wax 0.8 Palmitostearic acid 0.5Steareth-20 2.0 Sorbitan palmitate 1.0 Dimethicone 20 0.5 Propylpara-hydroxybenzoate 0.1 Propylene glycol 4.0 Glyceryl triacetate 1.0Phenoxyethanol 0.5 10% sodium hydroxide qs pH Water qs 100

EXAMPLE 4 Composition 4

% by weight relative to the total weight of the Ingredients compositionIvermectin 1.00 Glycerol 4.0 Aluminum magnesium silicate 1.0 Methylpara-hydroxybenzoate 0.2 Disodium EDTA 0.05 Citric acid monohydrate 0.05Isopropyl palmitate 4.0 Glyceryl/PEG 100 stearate 3.0 Self-emulsifiablewax 2.0 Palmitostearic acid 3.0 Steareth-20 3.0 Sorbitan palmitate 2.0Dimethicone 20 0.5 Propyl para-hydroxybenzoate 0.1 Propylene glycol 4.0Glyceryl triacetate 1.0 Phenoxyethanol 0.5 10% sodium hydroxide qs pHWater qs 100

EXAMPLE 5 Composition 5

The Compositions of Examples 5 and 6 are Formulated According to theFollowing Procedure

Aqueous Phase:

In a first beaker, disperse the acrylate/c10-30 alkyl acrylatecrosspolymer in water with Rayneri stirring at 800 rpm until ahomogeneous gel is obtained. Begin heating up to 65° C.-70° C., and thenadd the glycerol and the additives.

Oily Phase:

In a second beaker, incorporate the constituents of the oily phase andheat up to 70° C.-75° C., homogenize with Rayneri stirring at 400 rpm.

Active Phase:

In a third beaker, weigh the constituents of the active phase(solvent+additives).

Homogenize at approximately 500 rpm and introduce a magnetic bar.

Weigh the ivermectin in a weighing boat and then introduce it into thebeaker container the active phase.

Place this beaker on a magnetic stirrer until the ivermectin hasdissolved.

When the oily and aqueous phases are at 70° C., mix the two phases withRayneri stirring at 900 rpm for 10 min.

Allow the emulsion to cool to 40° C., add the active phase with Rayneristirring at 800 rpm for 10 minutes. Decrease at 700 rpm to 30° C.

Make up the volume with a sufficient quantity of water and adjust the pHto 6.3+/−0.3.

% by weight relative to the total weight of the Ingredients compositionIvermectin 1.00 Glycerol 4.0 Acrylate C10-30 alkyl acrylate 0.2crosspolymer Methyl para-hydroxybenzoate 0.2 Disodium EDTA 0.05 Citricacid monohydrate 0.05 Isopropyl palmitate 4.0 Cetyl alcohol 3.5 Stearylalcohol 2.5 Oleyl alcohol 2.0 Ceteareth-20 3.0 Sorbitan monostearate 2.0Dimethicone 200 20 cs 0.5 Propyl para-hydroxybenzoate 0.1 Propyleneglycol 2.0 Phenoxyethanol 1.0 10% sodium hydroxide qs pH Water qs 100

EXAMPLE 6 Composition 6

% by weight relative to the total weight of the Ingredients compositionIvermectin 1.4 Glycerol 4.0 Acrylate C10-30 alkyl acrylate 0.2crosspolymer Methyl para-hydroxybenzoate 0.2 Disodium EDTA 0.05 Citricacid monohydrate 0.05 Isopropyl palmitate 4.0 Cetyl alcohol 3.5 Stearylalcohol 2.5 Oleyl alcohol 2.0 Ceteareth-20 3.0 Sorbitan monostearate 2.0Dimethicone 200 20 cs 0.5 Propyl para-hydroxybenzoate 0.1 Propyleneglycol 2.0 Phenoxyethanol 1.0 10% sodium hydroxide qs pH Water qs 100

EXAMPLE 7 Example of Stability of the Compositions Described in Examples5 and 6

Assaying of the active agent by external calibration by HPLC.

Composition % of ivermectin in the composition at time t (in weeks)tested 0 4 8 12 Composition 5 100.2% 99.6% 100.7% 101.3% Composition 695.6%   97% 97.7% 95.8%

The results are expressed as % recovery relative to the theoreticalvalue, and demonstrate the very good chemical stability of theivermectin in the composition as a function of time.

EXAMPLE 8 Measurement of the Chemical Stability of Ivermectin as aFunction of pH in the Composition of Example 5

T0 T 1 month T 2 months % of % of % of pH active agent pH active agentpH active agent 4.0 105.7 4.36 106.5 4.34 102.3 5.02 109.3 5.14 104.25.14 97.3 6.28 107.6 6.2 104.1 6.18 102.1

These results show the very good chemical stability of ivermectin in thecomposition as a function of pH.

EXAMPLE 9 Study of Tolerance and of Acceptability of the Composition ofExample 5

A randomized single-blind intra-individual study was carried out on 15individuals with skin tending to be affected by rosacea. The compositionof Example 5 was tested in comparison with a gel and with an emulsionhaving compositions different from the compositions according to theinvention.

The individuals presented themselves three times in order to perform thevarious applications. In the course of each of the visits, 2 of thethree products were applied so as to cover each half-face. Each productwas tested twice during the study. After application and at each visit,the individuals filled in, for each product tested, a questionnaire forevaluating the clinical tolerance and the cosmetic acceptability.

The following clinical tolerance parameters were evaluated: stingingsensation, burning, dry skin, tightness or itching.

The following cosmetic acceptability parameters were evaluated:creaminess, texture, lack of a sensation of greasy and sticky skin,nourishing nature, feeling of comfort and of softness to the touch.

For all the tolerance parameters, the composition according to theinvention was judged to be well tolerated by the individuals, to thesame extent as the two other compositions.

In general, for all the acceptability parameters, the individuals gavetheir approval (good or excellent), with respect to the parameters,regarding the composition of the Example 5 in 76.66% of the cases whereit was tested. This formulation therefore tends to distinguish itselffrom the gel-cream composition, having a 66.66% approval, and from theother emulsion, having a 63.32% approval.

EXAMPLE 10 Study of Irritation Over 21 Days

A study of irritation over 21 days was carried out in order to test theirritation induced by the three compositions tested in the precedingexample. No product was considered to be irritant under the conditionstested.

Each patent, patent application, publication and literaturearticle/report cited or indicated herein is hereby expresslyincorporated by reference.

While the invention has been described in terms of various specific andpreferred embodiments, the skilled artisan will appreciate that variousmodifications, substitutions, omissions, and changes may be made withoutdeparting from the spirit thereof. Accordingly, it is intended that thescope of the present invention be limited solely by the scope of thefollowing claims, including equivalents thereof.

What is claimed is:
 1. A method for the treatment of rosacea, comprisingtopically applying onto the affected skin area of an individual in needof such treatment, a topical pharmaceutical composition which comprisesa thus effective amount of ivermectin, said topical pharmaceuticalcomposition being formulated as an emulsion, the topical pharmaceuticalemulsion comprising: an oily phase comprising dimethicone,cyclomethicone, isopropyl palmitate and/or isopropyl myristate, saidoily phase further comprising fatty substances selected from the groupconsisting of cetyl alcohol, cetostearyl alcohol, stearyl alcohol,palmitostearic acid, stearic acid and self-emulsifiable wax; at leastone surfactant-emulsifier selected from the group consisting ofglyceryl/PEG100 stearate, sorbitan monostearate, sorbitan palmitate,Steareth-20, Steareth-2, Steareth-21 and Ceteareth-20; ivermectin; amixture of solvents and/or propenetrating agents selected from the groupconsisting of propylene glycol, oleyl alcohol, phenoxyethanol andglyceryl triacetate; acrylate C10-C30 alkyl acrylate crosspolymergelling agent; and water; said emulsion being chemically stable over aperiod of time of 12 weeks.
 2. The method as defined by claim 1, whereinsaid at least one surfactant-emulsifier is present in an amount of up to15% by weight.
 3. The method as defined by claim 1, wherein saidivermectin is present in an amount of 0.1 to 5% by weight.
 4. The methodas defined by claim 1 wherein said mixture of solvents and/orpropenetrating agents is present in an amount of 0.1 to 20% by weight.5. The method as defined by claim 1, wherein said one or more gellingagents is/are present in an amount of 0.01 to 5% by weight.
 6. A methodfor the treatment of rosacea, comprising topically applying onto theaffected skin area of an individual in need of such treatment, a topicalpharmaceutical composition which comprises a thus effective amount ofivermectin, said topical pharmaceutical composition being formulated asan emulsion, the topical pharmaceutical emulsion comprising: 3 to 50% byweight of an oily phase comprising dimethicone, cyclomethicone,isopropyl palmitate and/or isopropyl myristate, said oily phase furthercomprising fatty substances selected from the group consisting of cetylalcohol, cetostearyl alcohol, stearyl alcohol, palmitostearic acid,stearic acid and self-emulsifiable wax; up to 15% by weight of at leastone surfactant-emulsifier selected from the group consisting ofglyceryl/PEG100 stearate, sorbitan monostearate, sorbitan palmitate,Steareth-20, Steareth-2, Steareth-21 and Ceteareth-20; 0.1 to 5% byweight of ivermectin; 0.1 to 20% by weight of a mixture of solventsand/or propenetrating agents selected from the group consisting ofpropylene glycol, oleyl alcohol, phenoxyethanol and glyceryl triacetate;0.01 to 5% by weight of acrylate C10-C30 alkyl acrylate crosspolymergelling agent; and water; said emulsion being chemically stable over aperiod of time of 12 weeks.
 7. A method for the treatment of rosacea,comprising topically applying onto the affected skin area of anindividual in need of such treatment, a topical pharmaceuticalcomposition which comprises a thus effective amount of ivermectin, saidtopical pharmaceutical composition being formulated as an emulsion, thetopical pharmaceutical emulsion comprising: 6 to 20% by weight of anoily phase comprising dimethicone, cyclomethicone, isopropyl palmitateand/or isopropyl myristate, said oily phase further comprising fattysubstances selected from the group consisting of cetyl alcohol,cetostearyl alcohol, stearyl alcohol, palmitostearic acid, stearic acidand self-emulsifiable wax; up to 15% by weight of at least onesurfactant-emulsifier selected from the group consisting ofglyceryl/PEG100 stearate, sorbitan monostearate, sorbitan palmitate,Steareth-20, Steareth-2, Steareth-21 and Ceteareth-20; 0.1 to 5% byweight of ivermectin; 0.1 to 20% by weight of a mixture of solventsand/or propenetrating agents selected from the group consisting ofpropylene glycol, oleyl alcohol, phenoxyethanol and glyceryl triacetate;0.01 to 5% by weight of acrylate C10-C30 alkyl acrylate crosspolymergelling agent; and water; said emulsion being chemically stable over aperiod of time of 12 weeks.
 8. The method as defined by claim 1,wherein: said oily phase comprises dimethicone and isopropyl palmitate,said oily phase further comprising fatty substances selected from thegroup consisting of cetyl alcohol and stearyl alcohol; said at least onesurfactant-emulsifier is selected from the group consisting of sorbitanmonostearate and Ceteareth-20; and said mixture of solvents and/orpropenetrating agents is selected from the group consisting of propyleneglycol, oleyl alcohol and phenoxyethanol.
 9. The method as defined byclaim 1, wherein: said oily phase comprises dimethicone, isopropylpalmitate, cetyl alcohol and stearyl alcohol; said at least onesurfactant-emulsifier is sorbitan monostearate and Ceteareth-20; andsaid mixture of solvents and/or propenetrating agents is a mixture ofpropylene glycol, oleyl alcohol and phenoxyethanol.
 10. The method asdefined by claim 1, said topical pharmaceutical composition furthercomprising one or more additives selected from the group consisting offlavor enhancers, preserving agents, stabilizers, humidity regulators,pH regulators, osmotic pressure modifiers, UV-A screening agents, UV-Bscreening agents and antioxidants.
 11. The method as defined by claim 1,said topical pharmaceutical composition further comprising one or moreadditives selected from the group consisting of glycerol, methylpara-hydroxybenzoate, disodium EDTA, citric acid monohydrate, propylpara-hydroxybenzoate and sodium hydroxide.
 12. A topically applicablestable pharmaceutical emulsion, comprising: an oily phase comprisingdimethicone, cyclomethicone, isopropyl palmitate and/or isopropylmyristate, said oily phase further comprising fatty substances selectedfrom the group consisting of cetyl alcohol, cetostearyl alcohol, stearylalcohol, palmitostearic acid, stearic acid and self-emulsifiable wax; atleast one surfactant-emulsifier selected from the group consisting ofglyceryl/PEG100 stearate, sorbitan monostearate, sorbitan palmitate,Steareth-20, Steareth-2, Steareth-21 and Ceteareth-20; ivermectin; amixture of solvents and/or propenetrating agents selected from the groupconsisting of propylene glycol, oleyl alcohol, phenoxyethanol andglyceryl triacetate; acrylate C10-C30 alkyl acrylate crosspolymergelling agent; and water; said emulsion being chemically stable over aperiod of time of 12 weeks.
 13. The topically applicable stablepharmaceutical emulsion as defined by claim 12, wherein said at leastone surfactant-emulsifier is present in an amount of up to 15% byweight.
 14. The topically applicable, stable pharmaceutical emulsion asdefined by claim 12, wherein said ivermectin is present in an amount of0.1 to 5% by weight.
 15. The topically applicable, stable pharmaceuticalemulsion as defined by claim 12, wherein said mixture of solvents and/orpropenetrating agents is present in an amount of 0.1 to 20% by weight.16. The topically applicable, stable pharmaceutical emulsion as definedby claim 12, wherein one or more gelling agents is/are present in anamount of 0.01 to 5% by weight.
 17. A topically applicable stablepharmaceutical emulsion, comprising: 3 to 50% by weight of an oily phasecomprising dimethicone, cyclomethicone, isopropyl palmitate and/orisopropyl myristate, said oily phase further comprising fatty substancesselected from the group consisting of cetyl alcohol, cetostearylalcohol, stearyl alcohol, palmitostearic acid, stearic acid andself-emulsifiable wax; up to 15% by weight of at least onesurfactant-emulsifier selected from the group consisting ofglyceryl/PEG100 stearate, sorbitan monostearate, sorbitan palmitate,Steareth-20, Steareth-2, Steareth-21 and Ceteareth-20; 0.1 to 5% byweight of ivermectin; 0.1 to 20% by weight of a mixture of solventsand/or propenetrating agents selected from the group consisting ofpropylene glycol, oleyl alcohol, phenoxyethanol and glyceryl triacetate;0.01 to 5% by weight of acrylate C10-C30 alkyl acrylate crosspolymergelling agent; and water; said emulsion being chemically stable over aperiod of time of 12 weeks.
 18. A topically applicable stablepharmaceutical emulsion, comprising: 6 to 20% by weight of an oily phasecomprising dimethicone, cyclomethicone, isopropyl palmitate and/orisopropyl myristate, said oily phase further comprising fatty substancesselected from the group consisting of cetyl alcohol, cetostearylalcohol, stearyl alcohol, palmitostearic acid, stearic acid andself-emulsifiable wax; up to 15% by weight of at least onesurfactant-emulsifier selected from the group consisting ofglyceryl/PEG100 stearate, sorbitan monostearate, sorbitan palmitate,Steareth-20, Steareth-2, Steareth-21 and Ceteareth-20; 0.1 to 5% byweight of ivermectin; 0.1 to 20% by weight of a mixture of solventsand/or propenetrating agents selected from the group consisting ofpropylene glycol, oleyl alcohol, phenoxyethanol and glyceryl triacetate;0.01 to 5% by weight of acrylate C10-C30 alkyl acrylate crosspolymergelling agent; and water; said emulsion being chemically stable over aperiod of time of 12 weeks.
 19. The topically applicable stablepharmaceutical emulsion as defined by claim 12, wherein: said oily phasecomprises dimethicone and isopropyl palmitate, said oily phase furthercomprising fatty substances selected from the group consisting of cetylalcohol and stearyl alcohol; said at least one surfactant-emulsifier isselected from the group consisting of sorbitan monostearate andCeteareth-20; and said mixture of solvents and/or propenetrating agentsis selected from the group consisting of propylene glycol, oleyl alcoholand phenoxyethanol.
 20. The topically applicable pharmaceutical emulsionas defined by claim 12, wherein: said oily phase comprises dimethicone,isopropyl palmitate, cetyl alcohol and stearyl alcohol; said at leastone surfactant-emulsifier is sorbitan monostearate and Ceteareth-20; andsaid mixture of solvents and/or propenetrating agents is propyleneglycol, oleyl alcohol and phenoxyethanol.
 21. The topically applicablestable pharmaceutical emulsion as defined by claim 12, furthercomprising one or more additives selected from the group consisting offlavor enhancers, preserving agents, stabilizers, humidity regulators,pH regulators, osmotic pressure modifiers, UV-A screening agents, UV-Bscreening agents and antioxidants.
 22. The topically applicable stablepharmaceutical emulsion as defined by claim 12, further comprising oneor more additives selected from the group consisting of glycerol, methylpara-hydroxybenzoate, disodium EDTA, citric acid monohydrate, propylpara-hydroxybenzoate and sodium hydroxide.
 23. The topically applicablestable pharmaceutical emulsion as defined by claim 20, furthercomprising glycerol, methyl para-hydroxybenzoate, disodium EDTA, citricacid monohydrate, propyl para-hydroxybenzoate and sodium hydroxide.